4.8 Article

Antigen-independent activation enhances the efficacy of 4-1BB-costimulated CD22 CAR T cells

Journal

NATURE MEDICINE
Volume 27, Issue 5, Pages 842-+

Publisher

NATURE PORTFOLIO
DOI: 10.1038/s41591-021-01326-5

Keywords

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Funding

  1. CHOP Immunotherapy Frontier Program
  2. Emily Whitehead Foundation
  3. V Foundation
  4. Curing Kids Cancer
  5. Society of Immunotherapy for Cancer Holbrook Kohrt Immunotherapy Translational Fellowship
  6. Breakthrough Bike Challenge Buz Cooper Scholarship
  7. Stand Up To Cancer (SU2C) Innovative Research Grant [SU2C-AACR-IRG 12-17]
  8. National Institutes of Health [R01GM104867]
  9. National Heart, Lung, and Blood Institute [HL125018]
  10. National Institute of Allergy and Infectious Diseases [AI124769, AI129594, AI130197]
  11. Japan Agency for Medical Research and Development [P20am0101108]
  12. NCI [K08CA194256, 1P01CA214278, R01CA226983]
  13. American Society of Hematology Scholar Award, NCI [1K99CA212302, R00CA212302]
  14. University of Pennsylvania-Novartis Alliance
  15. Cancer Research Institute Irvington Fellowship

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The study found CD22 to be an alternative immunotherapy target in ALL, with the pilot clinical trials of 4-1BB-based CAR T cells targeting CD22 showing unexpectedly low response rates. It highlights the beneficial role of autonomous signaling in CAR function and demonstrates the utility of bedside-to-bench-to-bedside translation in designing and implementing CAR T cell therapies.
While CD19-directed chimeric antigen receptor (CAR) T cells can induce remission in patients with B cell acute lymphoblastic leukemia (ALL), a large subset relapse with CD19- disease. Like CD19, CD22 is broadly expressed by B-lineage cells and thus serves as an alternative immunotherapy target in ALL. Here we present the composite outcomes of two pilot clinical trials (NCT02588456 and NCT02650414) of T cells bearing a 4-1BB-based, CD22-targeting CAR in patients with relapsed or refractory ALL. The primary end point of these studies was to assess safety, and the secondary end point was antileukemic efficacy. We observed unexpectedly low response rates, prompting us to perform detailed interrogation of the responsible CAR biology. We found that shortening of the amino acid linker connecting the variable heavy and light chains of the CAR antigen-binding domain drove receptor homodimerization and antigen-independent signaling. In contrast to CD28-based CARs, autonomously signaling 4-1BB-based CARs demonstrated enhanced immune synapse formation, activation of pro-inflammatory genes and superior effector function. We validated this association between autonomous signaling and enhanced function in several CAR constructs and, on the basis of these observations, designed a new short-linker CD22 single-chain variable fragment for clinical evaluation. Our findings both suggest that tonic 4-1BB-based signaling is beneficial to CAR function and demonstrate the utility of bedside-to-bench-to-bedside translation in the design and implementation of CAR T cell therapies.

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